1) Azithromycin was found to be a safe and effective first-line antibiotic for uncomplicated enteric fever in children based on a case series study of 83 children in Pakistan. 2) 90% of the children completed the study and were treated with a single daily 20mg/kg dose of azithromycin for 7 days. 3) Clinical cure was observed in 95% of children and bacteriological cure in 100% of children who were blood culture positive at baseline. Adverse effects were minor.

1. 1
ORIGINAL ARTICLE
Use of Azithromycin in Uncomplicated Enteric Fever as
First Line Antibiotic
WAQAR HUSSAIN, AHSAN AHMAD, ANITA LAMICHHANE, Asfand Tariq, Muhammad Aslam Khan
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Pak Paed J 2012; 36(2):
ABSTRACT
Introduction: Enteric fever is a systemic infection caused by the bacteria,
Salmonella enterica serovara Typhi (S.typhi) and Salmonella enterica
Author’s affiliations serovara Paratyphi (S. paratyphi A, B and C). Disease burden is more in
the developing countries. There is day by day increase in the multidrug
-------------------------------------------
resistant strains.
Correspondence to: Objectives: This study was conducted to assess the efficacy of
azithromycin as a first line antibiotic in the treatment of uncomplicated
Waqar Hussain, enteric fever.
Department of Paediatrics
Shaikh Zayed Hospital, Methods: This case series study was conducted in 83 children between
Lahore. Pakistan 2-12 years of age in Shaikh Zayed Hospital, Lahore, Pakistan. Those
patients who were Typhidot and/or blood culture positive included in this
E-mail: study and treated with azithromycin 20mg/kg/ single dose daily for 7
gwaq_122@hotmail.com
days.
Results: Out of the 83 children enrolled, 75(90.36%) completed the study
as the eight children lost to follow up. Male to female ratio was 1.6:1 with
common age group between 8-12 years. S.typhi was isolated in 5(6.67%)
cases and all achieve bacteriological cure by day 7. Mean (SD) duration
of fever at presentation was 5±3.07 days. Clinical cure was seen in 71
(94.6%) subjects. Mean day of response was 4 days. There was no death
in the study. No serious adverse event was observed in the study.
Conclusion: Azithromycin was found to be safe and efficacious for the
management of uncomplicated typhoid fever in a dose of 20
mg/kg/day per oral once a day for seven days.
Keywords: Enteric fever, Azithromycin, Salmonella typhi.
INTRODUCTION The global estimate of incidence of enteric fever
caused by S.typhi is 21 million cases causing
Typhoid fever is a systemic infection caused by 7,00,000 deaths each year3. Pakistan is a high
the bacterium Salmonella enteric serotype typhi, burden country with an annual incidence of
a member of the family Enterobacteriaceae. This 413/100,000 person/year2. Up to 93% of global
organism is an important cause of febrile illness in episodes occur in Asia, where Southeast Asia has
crowded and impoverished populations with an estimated incidence of 110 cases/1,00,000
inadequate sanitation that are exposed to populations4. S.typhi has no non-human vectors.
unsafe water and food1,2. Salmonella is human An inoculum as small as 1,00,000 organisms
restricted pathogen and transmission is feco-oral. causes infection in more than 50% of healthy
volunteers5. According to WHO (World Health

2. 2
Organization), the overall incidence of typhoid This is a case series study conducted in the
fever is 412 cases per 100,000 population per year department of Pediatrics, Shaikh Zayed Federal
in Pakistan6,7. Post Graduate Medical Institute, Lahore, Pakistan
from 1st May to 31st December 2011 with the prior
Because of the ready availability of the over-the
approval of the study protocol from the Ethical
counter antibiotics and subsequent resistance to
Committee of the Institutional Review Board of
these drugs in areas of endemicity, enteric fever
the concerned hospital. All the children between
is harder to treat6. Previously chloramphenicol
2-12 years of age who had typhidot IgM and/or
was used to treat this infection but in 1980
blood culture positive and diagnosed as
emergence of resistance limited its use8. This was
uncomplicated enteric fever were included in
followed by emergence of multidrug resistant
the study. All those children who fulfilled the
(MDR) strains (combined resistance to
following criteria were excluded from the study:
chloramphenicol, ampicillin and cotrimoxazole)
initially reported from India, Pakistan and Middle 1. Any child who was already taking other
East and then from all over the world. There is antibiotics for more than 48 hours
emergence of resistance to first line drugs like
2. Any child with poor oral intake.
chloramphenicol, ampicillin, cephalosporins8-10
also. 3. Any child with life threatening complication
of enteric fever(perforation, shock or seizures)
On the other hand, widespread use of
fluroquinolones led to the emergence of 4. Any patient with congenital or acquired
Salmonella Enterica serovar Typhi and Paratyphi immunodeficiency
strains with reduced susceptibility to
Written consent was obtained from
fluoroquinolones11. Widespread emergence of
parents/guardians of all children. On day of
multidrug resistant S. typhi has necessitated the
recruitment a complete medical, treatment and
search for other therapeutic options for typhoid
vaccination history was recorded. Complete
fever12,13.
physical examination was carried out. All the
Azalides are another class of antibiotics which children between 2-12 years of age who
have shown promise in the treatment of typhoid presented with the signs and symptoms of enteric
fever. Azithromycin is the first drug of this class fever and not taking antibiotics for more than 48
and studies comparing the efficacy of hours before presentation were started
azithromycin with cefixime in adults and children Azithromycin (20 mg/kg/day) dispersible
with typhoid fever have reported it to be safe tablet/suspension for seven days in a single daily
and efficacious14-16. In these circumstances, dose after sending CBC, blood culture and
recent clinical trials suggest that azithromycin sensitivity and typhidot IgM. After getting the
treatment (20 mg/kg/day upto a maximum of reports of blood culture and sensitivity and
1000 mg/day for 7 days in children) is useful for typhidot IgM, only those patients having blood
the management of uncomplicated typhoid culture or/and Typhidot IgM positive were
fever17. included. Study medication was dispensed and
monitoring instruction provided to each patient.
Azithromycin has excellent penetration into most
Children were treated at their home and
tissues and achievement in macrophages and
reassessed in the out-patient department on day
neutrophils that are >100 fold higher than
4, day 7 and day 30 after the start of the
concentrations in serum. These together with
treatment. On day 4 and day 7 temperature
azithromycin’s long half life of 72 hours, show
charts and symptom diary was evaluated with a
potential in the therapeutic management of
complete physical examination. Drug
enteric intracellular pathogens18. Few studies are
compliance was assessed by history and
exclusively reported in children19-20.
collecting the empty wrappers/bottles.
We conducted this case series study to assess the
Children who were blood culture positive were
safety and efficacy of single daily dose of
evaluated on day 7 also for repeat blood culture.
azithromycin for uncomplicated typhoid fever in
If the temperature increased or the clinical
children.
condition of the patient worsened or there was a
MATERIAL AND METHODS

3. 3
serious drug reaction, patient was taken off from 51 (61.44%) patients were male while 32(38.55%)
the study and treated with intravenous were female. 55(66.27%) belonged to middle
Ceftriaxone (75 mg/kg/day). All follow ups were class family while 28(33.73%) were from the lower
carried out in the out-patient department of the low socioeconomic background. Only 26(31.33%)
hospital. children had received antibiotics before
presentation. None of the patients had received
Types of outcome measures
prior typhoid vaccination. There was no mortality
Clinical Response: Resolution of symptoms and amongst the patients included in this study.
fever clearance (axillary temperature less than
Various clinical presentations of the patients at
380C for >72 hours) was considered sustained
the time of inclusion in this study are shown in the
after 7 days of treatment.
table 2 while the clinical findings of the patients
Microbiiological Response: Was considered when are shown in table 1.
the blood culture became negative for
TABLE 1: Physical Examination
salmonella typhi or para typhi after 7 days of
treatment. Clinical findings No. of patients % age
Coated tongue 67 89.30
Clinical Failure: Lack of resolution of symptoms by Hepatomegaly 52 69.30
day 7 or development of a major complication of Abdominal tenderness 20 26.67
typhoid fever (intestinal perforation, shock or Splenomegaly 15 20.00
seizures). Rose spots 05 06.67
Microbiological Failure: Blood culture positive on 8(9.6%) patients left the study. Out of these eight
day 7 for S.typhi or S. Paratyphi. patients, 5 did not come at day 4 for visit and 3
did not come for visit on day 7. So the data from
Relapse: Recurrence of fever along with signs and
these 8 patients could not be collected
symptoms of typhoid fever within 4 weeks of
completely. Only 75 patients completed the
completion of therapy, along with isolation of the
study. 37(49.33%) patients had temperature
organism in blood culture.
between 101-1020F followed by 31(41.33%)
patients with 100-1010F while 7(9.33%) had
temperature between 103-1040F. Fever clearance
RESULTS time (FCT) was 96 hours (4 days) in 62(82.66%)
We enrolled 83 children aged 2-12 years who patients. Fever settled at day 5 in 4(5.33%)
fulfilled the inclusion criteria. Mean age at the patients while on day 6 in 2(2.67%). 3(4%) patients
time of presentation was 7.7±3.07 years. Fig-1 had settlement of fever on day 7 while in 4(5.33%)
shows the age distribution of the patients. patients fever took more than 7 days to settle. In
5(6.67%) patients relapse was documented.
50.00% Blood culture was positive in five (6.67%) patients.
45.00% All of these patients achieved bacteriological
40.00% cure at 7th day. All the 75 patients had typhidot
35.00%
30.00% positive.
25.00% Treatment failure was observed in 4(5.3%)
20.00%
15.00%
children. These children were started on
10.00% intravenous antibiotic (Ceftriaxone) and all
5.00% improved by day 12-15.
0.00%
2-5 yrs 5-8 yrs 8-12yrs
Clinical features at the time of presentation and
at the time of follow-ups are given in table-2.
Fig 1: Frequency of age distribution
TABLE 2: Clinical characteristics of study children at baseline and follow up.
Clinical findings Visit 1 (Day 0) Visit 2 (Day 4) Visit 3 (Day 7)

4. 4
N % N % N %
Fever 75 100.00 13 17.33 4 5.33
Headache 23 30.70 5 6.67 0 0
Constipation 6 8.00 2 2.67 0 0
Diarrhea 15 20.00 3 4.00 0 0
Anorexia 16 21.00 10 13.33 3 4.00
Pain abdomen 27 36.00 4 5.33 1 1.33
Hepatomegaly 52 69.30 32 42.67 10 13.33
Splenomegaly 15 20.00 10 13.33 4 5.33
Coated tongue 67 89.30 50 66.67 10 13.33
DISCUSSION In our study, males had higher incidence of the
disease (male to female ratio of 1.6:1). This is in
Enteric fever is one of the commonest cause of accordance with the study done by Ansari et al
febrile illness and is the major reason for seeking 200223 and Bhattarai et al 200324.This study also
health service by the common people21. showed that fever was present in all the patients
Due to the emergence of multidrug resistance to followed by abdominal pain, headache and
drugs (Chloramphenicol, Ampicilin, Cotrimoxa- anorexia at the time of presentation which is
zole), the need of newer drugs for the treatment similar to other studies25,26.
of enteric fever is necessitated; the results with The emergence of the resistant strains of S.typhi
macrolides like Azithromycin is promising. In our has become an area of concern for decades.
study, a 7 day course of oral Azithromycin was Various trials have focused the mechanisms by
found to be highly effective, showing efficacy of which resistance to the first line drugs used in the
94.6%. The efficacy of Azithromycin has also been therapeutic management of enteric fever
established by other studies. Frenck et al 2004 develop. Hence the search for new drugs for
showed a similar comparable high percentage which S.typhi shows evidence of clinical
of clinical response to azithromycin at an response.
average rate which supports the present study19.
Failure rate was found to be 6.67% while the
In this study, the most common age group relapse rate was 5.33%. This has been observed in
affected was 8-12 years (45.33%), which is earlier studies on azithromycin11.
different from the study of Prajapati et al 2008
where result showed that common age group The limitation of this study was that it was not
was 1-5 years22. comparative and no data is available from
Pakistan on the role of Azithromycin in the
The fever clearance time was 96 hours (4days) in treatment of uncomplicated enteric fever to
62(82.66%) patients which is also comparable compare the results on this study.
with the study done by Frenck et al 2004 19, where
fever clearance time was 4.5 days. This study was a case series; however other
studies where comparison of Azithromycin was
The bacteriological cure was seen in all the seven done with intravenous ceftriaxone, the results
patients in our study. Similar response was were comparable. So, we suggest more studies
observed by the study done by Frenck et al of Azithromycin in comparison with other drugs in
200419, where bacteriological cure with our country so that the efficacy and safety of
Azithromycin was also 100%. In the present study, Azithromycin can be established.
Azithromycin was tolerated well. In only few
patients, abdominal symptoms like diarrhoea and
nausea was observed on 1st and 2nd day of
CONCLUSION
treatment. But these symptoms did not require
any therapy and settled by themselves although As there is rise in the emergence of multidrug
this cannot be proven, it is likely that many of the resistant strains, azithromycin may be considered
gastrointestinal tract symptoms were associated in uncomplicated enteric fever in a dosage of 20
with the underlying disease and not with the mg/kg/day per oral once a day for 7 days(max
treatment. 1000mg/day).

5. 5
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